Hyperthyroidism and its accompanying symptoms appears to affect approximately 1% of the population in the developed world. One cause of hyperthyroidism is Grave's Disease in which antibodies that stimulate the thyroid gland are overproduced. The negative effects of this condition include irritability, insomnia, and enhanced risk of congestive heart failure and atherosclerosis.
Current treatments include small-molecule drugs such as propylthiouracil and methimazole which counteract the action of thyroxin, surgery to remove all or part of the thyroid gland, and administration of radioiodide to diminish its function.
None of these approaches is completely satisfactory. The mechanism of counteraction of thyroxin by various antithyroxin drugs is unclear; surgery and radioisotope treatments are inherently risky. Thus, it would be helpful to provide a drug that lowers the thyroxin concentration in the serum without deleterious side effects.
The proteins and peptides of the present invention provide such a solution. They are closely related to a native protein, human serum albumin, and thus would be expected to have negligible side effects. Forms of HSA having only a minor modification at position 218 and fragments which contain this modification are capable of binding free thyroxin thus causing its inactivation.
One of these modified forms occurs naturally in familial dysalbuminemic hyperthyroxinemia (FDH). This is an autosomal dominant syndrome in subjects who have an elevated total serum thyroxin concentration but are clinically euthyroid. It is known that the elevated total thyroxin levels in serum in these patients is due to the presence of deviant HSA that exhibits enhanced binding to thyroxin.
Previous work by the present applicants based on intrinsic fluorescence properties of purified normal HSA and HSA obtained from an FDH patient using both steady-state and time-resolved methodologies showed that the patient had two HSA species with different affinities for thyroxin (Dughie, C. et al. Photochem Photobiol (1992) 57:416-419). The modification responsible for the thyroxin affinity of modified HSA has now been found. Thus, the invention provides, in purified and isolated form, modified forms of HSA and fragments thereof that are useful in diagnostic and therapeutic contexts.